E6-AP mutant mice carry a paternally imprinted Ube3a (ubiquitin protein ligase E3A) knock-out mutation and may be useful in studies of Angelman syndrome (AS).
Genetic background-dependent differences in the behavioral, EEG activity and seizure phenotypes are observed - see C57BL/6 Ube3a maternal deletion mice ("B6 AS" ; Stock No. 016590) and 129 Ube3a maternal deletion mice ("129 AS" ; Stock No. 004477).
Dr. Arthur Beaudet, Baylor College of Medicine
Mice that are heterozygous for the targeted mutation are viable and fertile. There is a reduced viability (9%) prior to weaning for homozygous offspring from heterozygous parents. Surviving homozygous mice display delayed growth and motor dysfunctions. No gene product (mRNA) is detected by Northern blot analysis in homozygous ES cells. In situ hybridization reveals no detectable expression in hippocampal neurons and Purkinje cells of heterozygotes with a maternal deficiency. Due to imprinting, with preferential expression of the maternal allele, heterozygous mice with a maternal deficiency display the phenotype while heterozygous mice with a paternal deficiency do not. Heterozygous mice with the maternal deficiency display reduced motor coordination, impaired long-term potentiation, and context-dependent learning abnormalities. Homozygous mice and heterozygous mice with a maternal deficiency have increased Purkinje cell cytoplasmic levels of TRP53, transformation related protein 53, and an increased susceptibility to tonic clonic seizures induced by handling. This mutant mouse strain represents a model that may be useful in studies of Angelman syndrome.
Mice with this Ube3a knock-out mutation are available on different genetic backgrounds - either C57BL/6 (Stock No. 016590) or 129 (Stock No. 004477). Born et al. 2017 Sci Rep. 7:8451 [PMID:28814801] describes genetic background differences in the behavioral, EEG activity and seizure phenotypes for these mutant mice. In summary, C57BL/6 Ube3a maternal deletion mice ("B6 AS") displayed robust behavioral impairments, spontaneous EEG polyspikes, and increased cortical and hippocampal power primarily driven by delta and theta frequencies. 129 Ube3a maternal deletion mice ("129 AS") demonstrated limited behavioral abnormalities, performed poorly on wire hang and contextual fear conditioning and exhibited a lower seizure threshold and altered spectral power. See that publication for more specific details.
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes and a loxP site was used to disrupt a 3 kb sequence including exon 2. The construct was electroporated into 129S7/SvEvBrd-Hprtb-m2-derived AB2.2 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to 129 mice.
|Allele Name||targeted mutation 1, Arthur L Beaudet|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||E6-AP-; E6AP-; Ube3A KO|
|Gene Symbol and Name||Ube3a, ubiquitin protein ligase E3A|
|Strain of Origin||129S7/SvEvBrd-Hprtb-m2|
|Molecular Note||A 3kb genomic region including exon 2 was replaced with a neo-loxP-hprt cassette via homologous recombination, resulting in deletion of 100 N-terminal amino acids in the encoded protein and a frameshift inactivating all putative protein isoforms. Homozygous mutant animals were identified by Southern blot and PCR genotype analysis.|
|Mutations Made By|| |
Dr. Arthur Beaudet, Baylor College of Medicine
The strain is maintained as a heterozygote due to variable homozygous lethality. Expected coat color is Agouti.
When using the 129 E6-AP- mouse strain in a publication, please cite the originating article(s) and include JAX stock #004477 in your Materials and Methods section.
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